Metformin and intervention in polycystic ovary syndrome
Robert J Norman, Warren J Kidson, Ross C Cuneo, Margaret R Zacharin
on behalf of the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group
MJA 2001; 174: 580-583
For editorial comment, see Lobo
PCOS and insulin resistance -
Published studies on metformin in PCOS -
What should doctors do? -
More articles on Endocrinology
- Polycystic ovary syndrome (PCOS) is classically characterised by
ovarian dysfunction (oligomenorrhoea, anovulation and
infertility), androgen excess (hirsutism and acne), obesity, and
morphological abnormalities of the ovaries (cystic enlargement and
- More recently, insulin resistance has been found to be common in
PCOS, along with an increased prevalence of other features of the
"metabolic syndrome", namely glucose intolerance, type 2 diabetes
mellitus, and hyperlipidaemia.
- Hyperinsulinaemia is likely to contribute to the disordered
ovarian function and androgen excess of PCOS.
- Reducing insulin resistance by lifestyle modifications such as
diet and exercise improves endocrine and menstrual function in PCOS.
These lifestyle modifications are the best initial means of
improving insulin resistance.
- Metformin, an oral hypoglycaemic agent that increases insulin
sensitivity, has been shown to reduce serum concentrations of
insulin and androgens, to reduce hirsutism, and to improve ovulation
rates. The effect of metformin alone on fertility rates is unknown.
Some studies suggest that metformin will reduce total body weight to a
small extent, but with a predominant effect on visceral adipose
- The effects of metformin on lipid abnormalities, hypertension or
premature vascular disease are unknown, but the relative safety,
moderate cost, and efficacy in reducing insulin resistance suggest
that metformin may prove to be of benefit in combating these
components of the "metabolic" syndrome in PCOS. Further properly
planned randomised controlled trials are required.
The definition of polycystic ovary syndrome (PCOS) is controversial
and subject to different interpretations. The typical presentation
(see Box 1) is with the clinical triad of obesity, androgen excess
(hirsutism and acne), and menstrual irregularity
(oligomenorrhoea, secondary amenorrhoea, and related
infertility). Patients may present with individual components of
the syndrome. For example, obese patients may simply present with
menstrual irregularity. Biochemical investigation usually shows
mild to moderate androgen excess (elevated total and free
testosterone, suppressed sex-hormone-binding globulin, and
increased adrenal and ovarian androgens). On ultrasonography,
ovarian morphology typically shows multiple cysts, increased
stroma and enlarged volume, although a normal appearance on
ultrasound does not exclude the diagnosis. There is considerable
phenotypic variability in the presentation, with not all patients
expressing all of these abnormalities. Lean individuals may have
As there is some phenotypic overlap between patients with congenital
adrenal hyperplasia or Cushing's syndrome and those with PCOS, the
work-up should include consideration of these differential
diagnoses. The prevalence of PCOS in premenopausal women is said to be
Hyperinsulinaemia, insulin resistance and impaired glucose
tolerance are very common in women with PCOS, particularly in those
with a body mass index (BMI) greater than 30,2,3 but insulin resistance
may occur in all women with PCOS, even those who are lean. Early-onset
type 2 (non-insulin-dependent) diabetes mellitus is a prominent
feature of PCOS in long-term follow-up studies. Insulin resistance
is largely the result of reduced insulin action in peripheral,
non-hepatic tissues such as skeletal muscle. In some cases the
insulin resistance is thought to be caused by genetic disorders of
insulin-independent serine phosphorylation of the Β-subunit of
the insulin receptor.1 Insulin resistance does not
improve with suppression of ovarian androgens, but responds to diet
and exercise, as in type 2 diabetes mellitus.
However, in women with PCOS the ovary does not appear
to be resistant to insulin when studied in vitro. Insulin
action in the ovary is mediated via the insulin receptor rather than
the type 1 insulin-like growth factor (IGF) receptor, which binds
IGF-I with high affinity and insulin with low affinity. Insulin
increases ovarian androgen production and may thereby impair
ovulation,4 suggesting that
hyperinsulinaemia may be pathogenetically important in PCOS.
Strategies that reduce insulin resistance, such as weight loss, diet
and exercise, have been shown to improve hyperinsulinaemia,
menstrual abnormalities, and ovulation rates.5 This forms the
basis for the potential use of metformin to treat the raised androgen
concentrations and menstrual disturbances in PCOS (see Box 2). There
is also emerging support for the use of other insulin-sensitising
agents, such as thiazolidenediones,6 but that is beyond the scope
of this review.
Metformin is a biguanide drug whose mechanism of action is poorly
understood, but it is known to enhance the peripheral action of
insulin without stimulating insulin secretion. The drug is widely
used in type 2 diabetes mellitus. Metformin is claimed to have a
multifactorial action, with prime effects on insulin sensitivity in
both the liver (where it reduces basal hepatic glucose production)
and in peripheral tissues (where it increases glucose uptake into
muscle in the insulin-stimulated state after meals). It reduces
blood glucose concentrations without causing hypoglycaemia
(except when used with alcohol). Other than in diabetes, metformin
has been used to improve insulin sensitivity in first-degree
relatives of people with diabetes, and people with upper-body
obesity and hypertension. The usual antidiabetic oral dose is
500-2500 mg daily.
A Medline search between 1966 and July 1999, covering the keywords
"polycystic ovary syndrome", "metformin", and "insulin
sensitizing drugs", identified 14 published original studies
containing primary data on the use of metformin in PCOS.7-20 Most of these
were observational studies, in which metformin was administered to
women with PCOS, with recording of biochemical and clinical effects
before and during treatment. The end-points studied varied from
glucose tolerance and insulin resistance to effects on ovulation and
pregnancy. Almost all studies were of short duration (4-6 months at
most); the clinical effects of metformin may take longer to be fully
The non-randomised studies found:
fasting insulin levels and insulin resistance in PCOS: Most
studies claim some reduction in fasting and glucose-stimulated
insulin levels as well as improvements in insulin sensitivity.
However, others fail to confirm these observations. There is no
apparent explanation on the basis of doses used, but the degree of
obesity is important in the response.
Effects on androgens and sex-hormone-binding
globulin: Most studies show beneficial effects on free
testosterone and sex-hormone-binding globulin levels. However,
this is not supported by other studies which are similar in design.
Effects on menstruation, ovulation and pregnancy:
Most publications do not deal with clinical outcomes. Those that do
indicate improvement in spontaneous menstruation in 20%-50% of
women. Some women became pregnant.
There were only five randomised trials comparing metformin with
placebo in PCOS to July 1999.7-10,18 A single-blind
crossover study showed no difference in insulin resistance between
the placebo and metformin arms of the trial after
treatment.7 Another study was unable to
show any benefit of metformin over placebo when both were used in
combination with diet.8 Neither of these two studies
addressed clinical reproductive outcomes. Of the remaining
randomised trials, two dealt with hormonal outcomes in obese and
non-obese women with PCOS, and showed an improvement in insulin
secretion, luteinising-hormone- stimulated
17-hydroxyprogesterone secretion, decreased levels of
luteinising hormone and free testosterone, and an increased level of
sex-hormone-binding globulin with metformin therapy.9,18 The third
looked at the effects of metformin with or without clomiphene citrate
on ovulation.10 Sixty-one women with PCOS
were randomly allocated to treatment with metformin or placebo, with
34% and 4%, respectively, ovulating after taking 1500 mg daily of
metformin or placebo. Of those who did not ovulate, 90% in the
metformin group responded to the addition of clomiphene citrate,
compared with only 4% in the placebo group. Pregnancy was not an
outcome measure in this study and few of the other studies reported
During the preparation of this review (through to January 2001), we
became aware of an additional 12 interventional (but not
placebo-controlled) studies of metformin in PCOS;21-31 these
studies reinforce the conclusions above. One important study
randomly allocated women to therapy with metformin or conventional
therapy for normalising menstrual activity and reducing androgen
excess (ethinyl oestradiol plus cyproterone acetate).30 This study
showed reductions in body weight, insulin levels and androgens with
metformin, but an increase in glucose intolerance with the
Two important randomised, double-blind, placebo-controlled
trials of metformin therapy in women with PCOS have recently been
published.32,33 In one, 23 women with
PCOS randomly allocated to treatment with either placebo or
metformin (500 mg three times daily) for six months showed
significant benefits in menstrual pattern, ovulation rate, insulin
sensitivity, serum free testosterone levels, and
17-hydroxyprogesterone levels without changes in body
weight.32 Almost 50% of the women
involved developed ovulatory cycles during an open-label,
long-term extension of the study. In the other, 20 women with obesity
and PCOS and 20 with obesity only were randomly assigned to either
placebo or metformin therapy (850 mg twice daily) for six months.
Metformin reduced visceral fat mass and improved
glucose-stimulated insulin levels, hirsutism and menstrual
pattern in those with PCOS. Two studies now show that metformin
The management of women with PCOS should go beyond therapy for
hirsutism and acne, menstrual irregularity and infertility.
Currently, it seems justified to screen all women with PCOS for
glucose intolerance or diabetes mellitus (with oral glucose
tolerance testing) and conventional cardiovascular risk factors
(smoking, blood pressure, hyperlipidaemia), and to institute
lifestyle modifications as necessary.
The literature supports a trial of metformin in patients with
anovulation, androgen excess and vascular risk factors, as these
abnormalities may be reduced. However, the long-term effects of
treatment with metformin on vascular risk factors, morbidity and
mortality are unknown. Clinically relevant end-points to follow may
include fasting serum glucose levels (with or without tests for oral
glucose tolerance and fasting plasma insulin level), fasting serum
levels of low-density lipoprotein (LDL) and high-density
lipoprotein (HDL) cholesterol, blood pressure, serum testosterone
level and hirsutism and acne, and menstrual pattern and fertility.
Side effects of metformin (which include diarrhoea and vitamin
B12 malabsorption) may limit compliance in some
patients. Lactic acidosis is a rare but serious side effect in
diabetes, but has not been described in PCOS.
Given the present lack of long-term safety data and demonstrable
efficacy in a large number of patients, we recommend that metformin
use be supervised by an endocrinologist or physician with expertise
in the area. Ideally, further research should be encouraged so that
outcomes can be scrutinised and regulatory issues can be carefully
A summary of recommendations for the use of metformin in PCOS is shown
in Box 3.
Background and evidence basis of recommendations
This article was commissioned by the
Endocrine Society of Australia, the Australian Diabetes Society and the
Australasian Paediatric Endocrine Group to review current published evidence
about the efficacy of the use of metformin in treating the polycystic
ovary syndrome in women. It was prepared by Robert J Norman, Warren J
Kidson, Ross C Cuneo and Margaret R Zacharin, and circulated to the Councils
of the above societies for consultation and suggested modifications.
- Lobo RA, Carmina E. The importance of diagnosing the polycystic
ovary syndrome. Ann Intern Med 2000; 132: 989-993.
Ehrmann E, Cavaghan M, Barnes R, et al. Prevalence of impaired
glucose tolerance and diabetes in women with polycystic ovary
syndrome. Diabetes Care 1999; 22: 141-146.
Legro R, Kunselman A, Dodson W, et al. Prevalence and predictors of
risk for type 2 diabetes mellitus and impaired glucose tolerance in
polycystic ovary syndrome: a prospective, controlled study in 254
affected women. J Clin Endocrinol Metab 1999; 84: 165-169.
Nestler JE, Jakubowicz DJ, de-Vargas AF, et al. Insulin stimulates
testosterone biosynthesis by human thecal cells from women with
polycystic ovary syndrome by activating its own receptor and using
inositolglycan mediators as the signal transduction system. J
Clin Endocrinol Metab 1998; 83(6): 2001-2005.
Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of
reproductive potential by lifestyle modification in obese
polycystic ovary syndrome: role of insulin sensitivity and
luteinizing hormone. J Clin Endocrinol Metab 1999; 84:
Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves
defects in insulin action, insulin secretion, ovarian
steroidogenesis, and fibrinolysis in women with polycystic ovary
syndrome. J Clin Endocrinol Metab 1997; 82: 2108-2116.
Acbay O, Gundogdu S. Can metformin reduce insulin resistance in
polycystic ovary syndrome? Fertil Steril 1996; 65: 946-949.
Crave JC, Fimbel S, Lejeune H, et al. Effects of diet and metformin
administration on sex hormone-binding globulin, androgens, and
insulin in hirsute and obese women. J Clin Endocrinol Metab
1995; 80: 2057-2062.
Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary
syndrome respond to insulin reduction with decreases in ovarian
P450c17 alpha activity and serum androgens. J Clin Endocrinol
Metab 1997; 82: 4075-4079.
Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of
metformin on spontaneous and clomiphene-induced ovulation in the
polycystic ovary syndrome. N Engl J Med 1998; 338: 1876-1880.
Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A.
Therapeutic effects of metformin on insulin resistance and
hyperandrogenism in polycystic ovary syndrome. Eur J
Endocrinol 1998; 138: 269-274.
Ehrmann DA, Cavaghan MA, Imperial J, et al. Effects of metformin on
insulin secretion, insulin action, and ovarian steroidogenesis in
women with polycystic ovary syndrome. J Clin Endocrinol
Metab 1997; 82: 524-530.
Morin Papunen LC, Koivunen RM, Tomas C, et al. Decreased serum
leptin concentrations during metformin therapy in obese women with
polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83:
Morin Papunen LC, Koivunen RM, et al. Metformin therapy improves
the menstrual pattern with minimal endocrine and metabolic effects
in women with polycystic ovary syndrome. Fertil Steril 1998;
Sir T, Castillo T, Munoz S, et al. [Effects of metformin on insulin
resistance in obese and hyperandrogenic women]. Rev Med Chil
1997; 125: 1457-1463.
Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in
polycystic ovary syndrome reduces hyperinsulinemia, insulin
resistance, hyperandrogenemia, and systolic blood pressure, while
facilitating normal menses and pregnancy. Metab Clin Exp
1994; 43: 647-654.
Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after
metformin therapy in polycystic ovary syndrome. Obstet
Gynecol 1997; 90: 392-395.
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome
P450c17 alpha activity and serum free testosterone after reduction
of insulin secretion in polycystic ovary syndrome. N Engl J
Med 1996; 335: 617-623.
Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is
associated with a decrease in plasma plasminogen activator
inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in
patients with the polycystic ovary syndrome. Metabolism
1997; 46: 454-457.
Zarate A, Hernandez M, Fonseca E, Ochoa RM. [Use of metformin to
treat adolescents with polycystic ovarian syndrome] Empleo de
metformin en manejo de adolescentes con el sindrome de ovarios
poliquisticos. Ginecol Obstet Mex 1997; 65: 504-507.
Morin-Papunen LC, Koivunen RM, Tomas C, et al. Decreased serum
leptin concentrations during metformin therapy in obese women with
polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83:
Unluhizarci K, Kelestimur F, Sahin Y, Bayram F. The treatment of
insulin resistance does not improve adrenal cytochrome P450c17
alpha enzyme dysregulation in polycystic ovary syndrome. Eur J
Endocrinol 1999; 140: 56-61.
Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced
resumption of normal menses in 39 of 43 (91%) previously amenorrheic
women with polycystic ovary syndrome. Metabolism 1999; 48:
De-Leo V, La-Marca A, Ditto A, et al. Effects of metformin on
gonadotropin-induced ovulation in women with polycystic ovary
syndrome. Fertil Steril 1999; 72: 282-285.
La-Marca A, Morgante G, Paglia T, et al. Effects of metformin on
adrenal steroidogenesis in women with polycystic ovary syndrome.
Fertil Steril 1999; 72: 985-989.
La-Marca A, Egbe TO, Morgante G, et al. Metformin treatment
reduces ovarian cytochrome P-450c17alpha response to human
chorionic gonadotrophin in women with polycystic ovary syndrome.
Human Reprod 2000; 15: 21-23.
De-Leo V, La-Marca A, Orvieto R, Morgante G. Effects of metformin
on insulin-like growth factor (IGF) I and IGF-binding protein I
(IGFBP-I) in polycystic ovary syndrome. J Clin Endocrinol
Metab 2000; 85: 1598-1600.
Unluhizarci K, Kelestimur F, Bayram F, et al. The effects of
metformin on insulin resistance and ovarian steroidogenesis in
women with polycystic ovary syndrome. Clin Endocrinol (Oxf)
1999; 51: 231-236.
Wang A, Li M, Lu C. Role of hyperinsulinemia in pathogenesis of
polycystic ovary syndrome. Chung Hua Fu Chan Ko Tsa Chih 1998;
Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L.
Metformin therapy decreases hyperandrogenism and
hyperinsulinemia in women with polycystic ovary syndrome.
Fertil Steril 2000; 73: 1149-1154.
Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and
metabolic effects of metformin versus ethinyl
estradiol-cyproterone acetate in obese women with polycystic ovary
syndrome: a randomised study. J Clin Endocrinol Metab 2000;
Moghetti P, Castello R, Negri C, et al. Metformin effects on
clinical features, endocrine and metabolic profiles, and insulin
sensitivity in polycystic ovary syndrome: a randomised,
double-blind, placebo-controlled 6 month trial, followed by open,
long-term clinical evaluation. J Clin Endocrinol Metab
2000; 85: 139-146.
Pasquali R, Gambineri A, Biscotti D, et al. Effects of long-term
treatment with metformin added to hypocaloric diet on body
composition, fat distribution, and androgen and insulin levels in
abdominally obese women with and without polycystic ovary syndrome.
J Clin Endocrinol Metab 2000; 85: 2767-2774.
Department of Obstetrics and Gynaecology, University of Adelaide,
Robert J Norman, FRANZCOG, FRCPA, Professor.
Prince of Wales Hospital, Randwick, and the Children's Hospital,
Warren J Kidson, MB BS, FRACP, Visiting Medical Officer; and
Visiting Endocrinologist, Royal Hospital for Women, Paddington,
Metabolic Research Unit, Department of Medicine, University of
Queensland, and Department of Diabetes and Endocrinology, Princess
Alexandra Hospital, Brisbane, QLD.
Ross C Cuneo, FRACP, PhD, Endocrinologist.
Department of Endocrinology and Paediatrics, The Royal Children's
Hospital, Melbourne, VIC.
Margaret R Zacharin, MB BS, FRACP, Endocrinologist.
Reprints will not be available from the authors.
Associate Professor R C Cuneo, Department of Medicine, Princess
Alexandra Hospital, Brisbane, QLD 4102.
Readers may print a single copy for personal use. No further
reproduction or distribution of the articles
should proceed without the permission of the publisher. For
permission, contact the
Australasian Medical Publishing Company.
Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>".
© 2001 Medical Journal of Australia.
1: Clinical presentations of patients with polycystic
- Oligomenorrhoea and anovulation
- Endometrial cancer
Obesity and metabolic disorders
- Insulin resistance
- Increased prevalence of type 2 diabetes mellitus
- Increased levels of total and low-density lipoprotein
- Decreased level of high-density lipoprotein
- Impaired fibrinolysis
- Increased prevalence of vascular disease and
|Back to text|
|Back to text|
3: Summary of recommendations for the use of metformin
in polycystic ovary syndrome (PCOS)
Many of the benefits claimed for metformin can be obtained by lifestyle
modification. This should be the first-line approach to overweight anovulatory
women with PCOS.
Infertile or oligomenorrhoeic
Metformin may benefit some women who have anovulatory PCOS. Daily doses
up to 2000 mg may improve the menstrual cycle, with the resumption of
ovulation, but an increase in pregnancy rates is not proven. Metformin
in combination with moderate doses of clomiphene citrate (50-100 mg) may
improve ovulation rates and is a cheaper option than the use of gonadotropins.
The value of metformin in reducing hyperandrogenaemia is small but detectable.
The findings of one controlled, long-term study support the use of metformin
in this situation.
Patients with the "metabolic"
Long-term use of metformin to reduce the sequelae of insulin resistance
in PCOS (hypertension, hyperlipidaemia, and premature vascular disease)
is untested but needs to be explored given the value of metformin in type
2 diabetes mellitus.
Potential side effects
While gastrointestinal side effects may reduce long-term compliance in
some patients, there are no known severe side effects of metformin in
patients with PCOS.
More research needed
There is an urgent need for more clinical trials before widespread use
of metformin in PCOS is accepted.
|Back to text|